1. Severe Myocarditis: A 2012 update…
Alain Combes
Service de Réanimation
iCAN, Institute of Cardiometabolism and Nutrition
Hôpital Pitié-Salpêtrière, AP-HP, Paris
Université Pierre et Marie Curie, Paris 6

2. Definition - Etiologies
«Myocarditis» is defined as inflammation of the heart muscle
Histology: cellular infiltrate and myocyte necrosis
Etiologies:
Infectious diseases
Viruses: Coxsackie, Adenovirus, HIV, Parvovirus B19, HHV6, (H1N1)
Bacteria
Parasites (Toxoplasma, Chagas)
Fungi
Hypersensitivity (Drugs)
Autoimmune and systemic diseases
Lupus, Wegener, Eosinophilic, Sarcoidosis, Giant cell
Myocardial toxins (Cocaine, chemotherapy)
Peripartum

3. 6.3 millions military recruits over 25 yrs
126 non-traumatic sudden deaths, autopsy performed
10% of myocarditis-related deaths

4. Clinical manifestations
From asymptomatic EKG abnormalities to overt cardiac failure…
Clinical features:
Preceding viral illness, flu-like syndrome
Fever
Chest pain, mimicking acute coronary syndromes
Tachycardia
Arrhythmia
Sudden death:
10% of cases (Eckart, AnnIntMed, O4)
Clinical signs of heart failure
Minimal, slow evolution
Fulminant, leading to refractory cardiogenic shock in a few days

5. EKG EKG findings May be normal… Sinus tachycardia
Diffuse ST-T wave abnormalities
Prolonged QT interval
Bundle branch block (LBBB++)
Myocardial infarction pattern
Complete heart block
Supraventricular tachyarrhythmias
Ventricular tachyarrhythmias
May be normal…

6. EKG mimicking AMI

7. EKG: LBBB

8. Laboratory Findings

9. Biology: Troponin (Smith, Circ, 97)

10. Many patients with acute/fulminant myocarditis will undergo coronary artery angiography…

11. Other laboratory findings
Non specific tests
Leucocytosis/leucopenia, Eosinophilia+++
Mononucleosic syndrome
Sedimentation rate, CRP, PCT…
Specialized tests
Virological diagnosis
Serology (limited value)
Cultures: throat and stools
PCR (blood, CSF, tissues)
Inflammation:
Antinuclear Ab, ANCA, Angiotensin Conversion Enzyme
Research tests
Autoantibodies (mitochondria, myosin, b-receptor)
Immunohistochemical myocardial studies (research)

12. Doppler Echocardiography

13. Fulminant myocarditis
Markedly decreased LV EF
Near normal LV dimension
Increased septal thickness
Acute myocarditis
Dilated LV
Normal septal thickness

14. Doppler Echocardiography
Other findings
Regional wall motion abnormalities
Diastolic dysfunction
Change in echocardiographic image texture:
Increased brightness
Heterogeneity
Thrombi
Pericardial effusion

15. The new diagnostic gold standard?
Cardiac MRI…
The new diagnostic gold standard?

16. Cardiac MRI Combination of T1-weighted and T2-weighted
Gadolinium contrast-enhanced MRI +++
Visualize localization, activity and extent of inflammation
One or several foci in the myocardium
Foci most frequently located in lateral free wall
Frequent subepicardial lesions
Can guide myocardial biopsies+++

18. Still indication for myocardial biopsies?

19. Histology: Dallas Criteria
3 histological grades (Aretz, Hum Pathol, 87)
Active Myocarditis :
Cellular infiltrate +, myocyte necrosis +
Borderline Myocarditis :
Cellular infiltrate +, myocyte necrosis -
Negative Biopsy :
Cellular infiltrate -, myocyte necrosis -
Distribution and diffusion of the cellular infiltrate
Focal, confluent or diffuse
Mild, moderate, severe
However, low to moderate sensitivity/specificity

20. Histology: Dallas Criteria
Borderline
Active

23. Grade 1, Level B: .

24. Prognosis

25. Prognosis McCarthy, NEJM, 2000 Survie sans transplantation P=0.05
(15 patients)
P=0.05
(132 patients)

28. 41 patients refractory cardiogenic shock due to fulminant myocarditis
41 patients refractory cardiogenic shock due to fulminant myocarditis
Mean age 38±12 years
66%, women
Mechanical assistance
Thoratec BiVAD (n=6) or
ECMO (n=35)

30. 4 (10%) patients had heart transplantation
Long term survival: 68%
4 (10%) patients had heart transplantation
Independent predictors of ICU death determined at admission:
SAPS II >56 (OR, 10.23) and troponin Ic >12 microg/L (OR, 7.49)

31. Complete follow-up for 26 survivors
Median follow-up was 525 [92–2400] days
Mean LVEF was 57±9%
≥60% for 12 non-transplant and all 4 transplanted
40–60% for 10 nontransplanted survivors
21 patients had percutaneous femoral ECMO
10 still complained of paresthesia/peripheral neurological defect
2 had persistent leg ischemia requiring surgical repair for 1 and amputation for the other

36. Treatment

37. Treatment Supportive care always indicated Mechanical assistance +++
Bed rest
Diuretics, vasodilators
ACE inhibitors, angiotensin-receptor blockers
Aldosterone antagonists
b-blockers, (with caution in the acute phase)
Vasopressors/inotropic agents in case of shock
Mechanical assistance +++
May be urgently needed if fulminant form or rapid deterioration of hemodynamic status
Patients should rapidly be transferred to experienced centers
Bridge to recovery:
ECMO+++, First line assistance
(Heart transplantation)

38. ECMO vs. BiVAD for fulminant myocarditis?

39. P = ns

41. T bilirubin mol/dl
Creatinine mol/dl

43. Long term survival: 68%, 4 (10%) patients had heart transplantation
Independent predictors of ICU death determined at admission:
SAPS II >56 (OR, 10.23) and troponin Ic >12 g/L (OR, 7.49)

44. Specific/Novel treatments
Immunosuppression
First line therapy if
Giant cell
Systemic autoimmune diseases
Corticosteroids
Cyclosporine, Tacrolimus
Azathioprine
Immunomodulation/Stimulation
IV Immune globulins
Interferon
Antiviral agents, vaccination

45. Myocarditis Treatment Trial
111 randomized patients, LVEF<45%
Histologically proven myocarditis
Immunosuppression protocol
Placebo vs prednisone + Cyclosporine or azathioprine
Mason, NEJM, 1995

46. IV immune globulin 62 patients with DCM, randomized, LVEF<40%
McNamara, Circ, 2001
62 patients with DCM, randomized, LVEF<40%
Placebo vs IVIg
P = NS

47. Tailored immune-modulating strategies
Liu, Circ, 2001
Phase I
Phase II
Phase III

48. Immunomodulation vs Immunosuppression
Interféron b chez les patients avec persistance virale entero-adénovirus
Kuhl, Circ, 2003
22 patients, Dysfonction VG, génome viral +
Interféron: Clearance virus, amélioration FE
Immunosuppression:prednisone+imurel
Frustaci, Circ, 03
41 patients, myocardite active, Dysfonction VG
21 répondeurs, 20 non rep
Répondeurs: AutoAC +, génome viral- (sauf Hep C)
Wojnicz, Circ 01
84 patients CMD, HLA surexprimé sur myocytes
Traitement de 3 mois
Amélioration dans groupe traité: 71% vs 31%

56. Conclusion Myocarditis is a rare and severe condition
Especially the fulminant form
Diagnosis based on clinical features, EKG, Echo, Troponin, MRI
Myocarditis can mimic acute coronary syndromes
Mechanical circulatory assistance may be urgently needed if rapid hemodynamic deterioration
Immunosuppression during the acute phase
Giant cell
Systemic autoimmune diseases
Significant progresses in the understanding of the pathophysiology of the disease in recent years
Help design tailored immune-modulating strategies

57. La Pitié: Louis XIV, 1656… To 2012…
La Chapelle
Institut de Cardiologie